Process for producing nicotinic acid from acrylonitrile



United States Patent 3,246,000 PROCESS FOR PRODUCING NICOTINIC ACID FROM ACRYLONITRILE Manuel M. Baizer, St. Louis, Mo., assignor to Monsanto Company, a corporation of Deiaware No Drawing. Filed Dec. 18, 1963, Ser. No. 331,355 6 Claims. (Ci. 260-4055) The present invention concerns a procedure for preparing nicotinic acid from acrylonitrile. The invention is also directed to particular steps of the procedure and to one of the intermediate products obtained in the procedure, viz. l,8-diamino-4-aminornethyloctane.

Nicotiuic acid, i.e., pyridine-3-carboxylic acid, is a known compound of recognized value as an anti-pellagra vitamin. It occurs in liver, yeast, etc,, and can be prepared by oxidation of nicotine extracted from tobacco leaves.

It is an object of the present invention to provide a source of nicotinic acid. It is a further object to provide a procedure for converting acrylonitrile to nicotinic acid. Acrylonitrile is an abundantly available, inexpensive industrial raw material produced by several different commercial processes. It has not previously been proposed, however, to convert acrylonitrile to nicotinic acid.

In accordance. with the present invention acrylonitrile is converted, to nicotinic acid by a series of steps involving reductive trimerization of the acrylonitrile to 1,3,6- tricyanohexane, reduction and cyclization to 3-(4-aminobutyD-piperidine, dehydrogenation to 3-(4-aminobutyl)- pyridine, and oxidation to pyridine-3-carboxylic acid. In the reduction step, 1,8-diamino-4-aminomethyloctane is generally found along with the 3(4-aminobutyl)-piperidine but can be cyclizedto the piperidine under the reaction conditions.

Representative procedures in accordance with the invention can be pictured:

oxidation 0 0 O H (nitric acid) 3,246,000 Patented Apr. 12, 1966' tion. This reaction can be conducted under general electrolysis conditions but to direct the reaction to tri-rncrs other than dimers, only limited amounts of proton donors. such as water and acetonitrile should be present, although some proton donor is needed to avoid direction of the reaction to higher polymers, and it is also desirable to. exclude free-radical catalysts or anions capable of generating anionic polymerization of acrylonitrile. Any other reductive means capable of reductively trimerizing acrylonitrile to 1,3,6-tricyanohexane can be employed in this step of the process.

The tricyanohexane is then reduced by reducing means, capable of reducing cyano groups to amino groups. Hy-. drogenation procedures are particularly suitable.

The hydrotrimer, i.e., 1,3,6-tricyanohexane, will generally be obtained to some extent even if large amounts of proton donor are present during the electrolysis, but it is preferred to maintain such amounts relatively low in order to obtain suitable yields. The electrolysis is preferably conducted in a catholyte compound of salt, acrylonitrile, a proton source and possibly also a co-solvent (which can also be the proton source). When water is the proton donor, it prefer-ably ranges from 3% or so up to'about 20% by Weight of the catholyte. The acrylonitrile often constitutes 20 to 40% by weight of the, catholyte, and the electrolyte salt often 40 to 70% by weight of the acrylo: nitrile and salt, although the percent of the salt is often lower when no co-solvent is present. Acetonitrile can also be employed as a proton donor. Further explanations of various procedures and conditions for obtaining the 1,3,6-dicyanohexane are set forth in my aforesaid copending application, S. N. 260,853.,

Example 1 An electrolysis was conducted with a catholyte of 60 grams tctraethyla-mmonium p-toluenesulfonate, 3 grams water and grams acrylonitrile, and an anolyte of 30 ml. 82% methyltributylannnonium methylsulfate diluted with 20 ml. water. A current of 1.5 to 2.0 amperes was passed for 3.5 ampere-hours. The catholyte was diluted with water and extracted with methylene dichloride. A liquid residue isolated from the extracts was distilled, a 4.3 gramfraction having B.P. ISO- C./0.25 mm., 11 1.4670, M.W. 145.

Anal.Found: C, 65.76; H, 7.15; N, 24.86.

The high boiling oils obtained in diiferent electrolyses of acrylonitrile were collected. One portion boiling 134-178 0.2 mm. was isolated by extracting the catholyte of Example 6 with methylene dichloride. Another was obtained from electrolysis of acrylonitrile in 91% quaternary ammonium sulfonate Without a co-solvent. Still other portions were obtained in the residue of electrolytic adip onitrile preparations. The oils were combined and then separated by distillation, one liquid boiling 186.- 200/ 0.2 mm. and the second, 264/ 0.05 to 288/ 0.18 mm. Analysis indicated the first to be a hydrotrimer, 1,3,6-tricyanohexane, which was confirmed by preparation of derivatives.

Anal.Calcd for C H N C, 67.05; H, 6.88; N, 26.07; mol. wt., 161.2. Found: C, 66.81; H, 7.02; N, 24.72.

Hydrolysis yielded 1,3,6-tricarboxylhexane, M.P. 112' compared to the reported Ill-112 C.

Anal.Calcd for C H O C, 49.54; H, 6.47; neutr. equiv. 72.7. Found: C, 49.40; H, 6.55; neutr. equiv. 73.2.

A sample of the tricarboxyhexane showed no depression in melting point when mixed with 1,3,6-tricarboxyhexane obtained by the novel procedure of preparing diethyl alpha-(3-cyanopropyl), alpha-(Z-cyanoethyl) malonate from alpha-(3-cyanopropyl) malonate and acrylonitrile, and hydrolyzing withconcentrated hydrochloric acid. The higher boiling oil above was shown by analysis to be an acrylonitrile hydrotetramer, which could' be formulated as 1,3,5,8-tetracyanooctane or 1,3,6,8-tetracyanooctane. V The tetraethyl esters corresponding to both of these structures were independently prepared andcompared with the tetraethylesters obtained by hydrolysis and esterification of the hydrotetramer, and both nuclear magnetic resonance and vapor phase chromatographic examination showed the esters from the hydrotetramer to be mixtures of those obtained from the two structures. The 1,3,6,8-tetracarbethoxyoctane was obtained by cyanoethylating tetraethyl 1,1,4,4butanetetracarboxylate with acrylonitrile in caustic methanol to form tetraethyl, 1,4- bis(2- .cyanoethyl)-1,1,4,4-butanetetnacarboxylate, hydro lyzing with concentrated hydrochloric acid, esterifying with ethanol sulfuric acid, and fractionating, 166-184/ 0.08-0.10 mm. n 1.4480.

Anal.-Found: C, 59.41; H, 8.43.

. The 1,3,5,S-tetracarbethoxyoctane was obtained by base catalyzed addition of diethyl alpha-(2-cyanoethyl) malonate to methyl alpha-(3-cyanopropyl) acrylateto form 1,8-dicyano-3,3 dicarbethoxy 5 carbmethoxyoctane, followed by hydrolysis with concentrated hydrochloric acid and esterification with ethanol sulfuric acid. Upon distillation the vapor fraction was obtained at 180/ 0.3 mm. to 182/ 0.25 mm., n 1.4770.

Anal.Found: C, 59.46; H, 8.21.

The 1,4-bis (Z-cyanoethyl) -1, 1,4,4-butanetetracarboxylate intermediate above was crystallized from t-butylalcohol, M.P. 9394.

Anal.Calcd for C22H32N208: C, H, N, 6.19. Found: C, 58.24; H, 7.17; N, 6.15.

Example 2 To a 300 ml. bomb were charged 40 grams of acrylonitrile hydrotrimer (1,3,6-tricyanohexane), 70 grams an hydrous ammonia and 3 grams Raney cobalt (under ethanol). The bomb was heated to 150 C. and pressured to about 3000 p.s.i. with hydrogen, and rocked under these conditions for about 24 hours with hydrogen being added at intervals to maintain pressures of about 3000 to 4000 p.s.i. The reaction mixture was distilled with an 18" Vigreux column, a 14.5 gram-fraction being obtained at 75-90 C./ 0.2 mm., 11, 1.4822 and an 18.4 gram fraction of 1,8-diamino-4-aminomethyl octane at 98.5103 C.i0.20-0.25 mm; n 1.4848. The residue was combined with the reaction mixture of a duplicate hydrogenation, and distilled, a lower boiling fraction of 14.1 grams being obtained at- 71 95 C./0.20-0.25 mm., and a 9.8 gram triamine fraction at 102-106 C./0.30-0.35 The lower boiling fractions of the distillations solidified upon cooling. A sample of the solid was dissolved in ethanol, treated with a few drops of concentrated hydrochloric acid, evaporated to dryness, recrystallized from alcohol and dried, M.P. (capillary) 226- 228 C. The reported value [1. Am. Chem. Soc., 67, 1258 (1945)] for 3-(4-aminobutyl)piperidine di-hydrochloride is 228.8230 C.

Anal. for C H N Cl .-Calcd: C, 47.16; H, 9.68; N,

12.22. Found: C, 46.05; H, 9.65; N, 11.46.

Another sample was converted to the p-toluenesulfonamide salt, C H N S O and recrystallized from water, M.P. (capillary) 146-147" C. (reported 143-144? C.).

Example 3 A300 ml. bomb was charged with Raney cobalt, 3

grams, 1,8-diamino-4-aminomethyloctane, 21 grams, and

.20 gramsof anhydrous ammonia. The bomb was pres- .sured with hydrogen and heated at 150 C. for about three hours, pressures of about 3750 p.s.i. being attained. The

0.10 mm., which had infrared spectra and refractive inv dex identical .to that of 3-(l-amiuobutyflpiperidine, the

conversion being 25%. An 11' gram fraction-got the s tart ing triamine was recovered in the distillation.

Example 4 v 7 I To 6.5 gram portion of the 3-(4-aminobutyl)piperidine in benzene, 9.1 grams of acetic anhydride was slowly added to acetylate the two amino groups. After the exothermic reaction subsided the reaction mixture was refluxed for 1 hour and volatile material was then evoporated to leave a syrup which was dissolved in benzene, washed with bicarbonate solution and with water, and dried over magnesium sulfate. The solvents were removed to leave 9 grams of the diacetylated syrup. The syrup was mixed with a gram of 10% palladium on carbon catalyst and heated at 200-250 C. for about four hours as about 1135 ml. of gas was collected. The reaction mixture was treated with methylene chloride, and filtered, the catalyst being washed thoroughly with methylene chloride. The methylene chloride was removed by warming over a water bath to leave 6.9 grams of liquid having a strong pyridine odor [theory for 3(4-.acetylaminobutyl) pyridine is 7.2 grams]. condenser, 75 ml. of concentrated nitric acid was slowly added, and following the exothermic reaction the mixture was slowly warmed to and maintained at such temperatures for about 12 hours. The product was evaporated nearly to dryness, dissolved in hot water, treated with charcoal, filtered, concentrated by evaporation, chilled in ice and about 1 gram of crystals obtained by filtration. The mother liquor was further concentrated and a second 1 gram crop of crystals obtained. The combined crystals were dissolved in hot water, treated with Na HPO -7H O, the pH adjusted to 3-4 with hydrochloric acid, concentrated, chilled in ice and a yellowwhite solid separated by filtration. The solid was airdried, digested with alcohol, decanted through a filter, concentrated to yield a crop of crystals, M.P. (capillary) 225-232 C. A second crop of crystals of lower melting point was possibly contaminated with nitrate. The first crop was recrystallized from alcohol, M.P.(capillary) 232-236 C., and had an infrared spectrum identical to that of nicotinic acid. a

Example 5 A 1 liter bomb was charged with 30 grams of the electrolytically produced hydrotrimer of acrylonitrile, 2 grams Raney cobalt in 25 ml. ethanol, and 106 grams ammonia. The hydrotrimer was charged first, followed by the catalyst slurry and the bomb was then sealed and cooled in an acetone-Dry Ice bat-h and the ammonia was introduced and the bomb allowed to come to room temperature and pressured to 600 p.s.i. with hydrogen. The bomb was then heated to about 140 C. with periodic addition of hydrogen, pressures of 4000 p.s.i., being attained, and maintained under pressure overnight. The bomb was vented and the pro-duct taken up in ethanol. The catalyst was removed by filtration and the alcohol by vacuum to leave a 33 gram residue. The product was distilled, combined with product of a similar hydrogenation over pelleted cobalt catalyst, and then redistilled through a Todd column, and 11.7 gram fraction of 1,8-diamino-4-aminomethyloctane being obtained at 161-163/4 mm., n 1.4883. Infrared spectra indicated -NH groups but no CN groups.

Anal.--Calcd for C H N C, 62.43; H, 13.29; N, 24.28. Found: C, 62.15; H, 13.36; N, 23.27.

In general reduction procedures suitable for reducing cyano groups to amino groups can be employed in the reduction step. Catalytic hydrogenation is the usual method, metallic catalysts usually being employed. Nickel catalysts, e.g., nickel on kieselguhr or Raney nickel, can be employed. Platinum, platinum oxide and palladium 'catalysts are also suit-able, e.g., Adams platinum catalyst or palladium on cobalt or charcoal. The hydrogenation is usually conducted at temperatures of -l50 C., al-

To the product under a reflux through higher or lower temperatures can be employed, particularly, for example, if a catalyst such as a Raney nickel especially adapted for use at low temperature and pressure is employed. The pressures employed are those suitable for catalytic hydrogenation which are superatmospheric pressures and generally above 100 p.s.i. and usually from several hundred p.s.i. up to several thousand p.s.i. or higher, e.g., 500 p.s.i. to 5000 p.s.i. The formation of secondary products can be suppressed to some extent by employing relatively large amounts of catalysts to effect rapid hydrogenation The use of ammonia during the hy dr-ogenation serves to direct the hydrogenation toward the open-chain triamine at the expense of cyclization to the substituted piperidine. Howexer, unless very large amount-s of ammonia are used, some of both products are ordinarily obtained. For example, utilizing, on a weight basis, from less than an equivalent amount of ammonia to twice the amount of ammonia compared to the 1,3,6- tri'cyanohexane, both the open-chain triamine and the substituted piperidine are obtained, whereas, when the amount of ammonia is three-times or more by weight that of the tricyanohexane, the product is practically exclusively the open-chain triamine. The cyano groups can also be reduced by other known means for reducing cyano groups to amino groups, e.g., reduction with sodium and alcohol or with lithium aluminum hydride. The 1,8-diamino-4-aminomethyloctane obtained by hydrogenation or other reduction, can, if desired, be converted to the 3-(4- aminobutyD-pyridine by treating the referred-to octane under hydrogenation condition-s taught herein for the production of 3-(4-aminobutyl)-piperidine from tricyanohexane, which are in general catalytic hydrogenation condition, optionally in the presence of ammonia.

The dehydrogenation step can be conducted according to ordinary dehydrogenation procedures for preparing aromatic compounds. In general this involves heating the substituted piperidine compound with a catalyst. The usual hydrogenation catalysts can be used for such dehydrogenations. Platinum and palladium catalysts are very suitable, generally 'being employed on the usual supports. Nickel catalysts can also be used, as can various metal oxide catalysts, and metallic catalysts in general. Various temperatures can he employed for the dehydrogenation, the advantage of particular temperatures depending upon the catalyst. For example temperatures from less than 100 C. to more than 350 C. can be employed, as can other higher and lower temperatures.

In the oxidation step, the aminobutyl group can be oxidized by methods commonly used to oxidize alkyl groups to carboxyl groups, e.g., oxidation with nitric acid, alkaline permanganate or gaseous oxygen under the usual conditions, or by employing other oxidizing agents.

The nitric acid can be added in concentrated form to the pyridine compound, followed by warming, e.g., from 50 to C. or so to complete the oxidation, but dilute nitric acid or more or less rigorous temperature conditions can also be employed. Other known procedures for oxidizing alkylated benzenes to 'benzoic acids can suitably be employed in the oxidation step.

What is claimed is:

1. The method of preparing nicotinic acid which comprises reductively trimerizing acrylonitrile to tricyanohexane, hydrogenating the cyano groups, heating with dehydrogenation catalyst to obtain 3-(4-aminobutyD-pyridine, and oxidizing the aminobutyl group to a carboxyl group to obtain nicotinic acid.

2. The method of preparing nicotinic acid which comprises electrolyzing a salt solution of acrylonitrile in contact with a cathode to obtain 1,3,6-tricyanohexane, hydrogenating the 1,3,6-tricyanohexane in the presence of ammonia to obtain 3-(4-aminobutyl)-piperidine, heating with dehydrogenation catalyst to obtain 3-(4-aminobutyl)-pyridine and oxidizing to nicotinic acid.

3. The method of claim 2 in which the hydrogenation also produces 1,8-diamino-4-aminomethyloctane which is converted to 3-(4-aminobutyl)-piperidine by continuing the hydrogenation conditions.

4. The method of claim 2 in which the amino groups are acylated prior to the dehydrogenation.

5. The method of preparing nicotinic acid which comprises hydrogenating the cyano groups of 1,3,6-tricyanohexane and heating with dehydrogenation catalyst to obtain 3-(4-aminobutyl)-pyridine, and oxidizing the aminobutyl group to a carboxyl group to obtain nicotinic acid.

6. The method of preparing nicotinic acid which c-orn prises electrolyzing acrylonitile in a quaternary ammonium aromatic su lfonate solution containing only a small amount of water to obtain 1,3,6-tri'cyan0hexane, hydrogenating the cyano groups over a metallic hydrogenation catalyst at temperatures of about 100 to C. in the presence of ammonia with hydrogen pressures of 100 to 5000 p.s.i., and dehydrogenating 'by heating over a dehydrogenation catalyst to obtain 3-(4-aminobutyl)-pyridine and oxidizing with nitric acid to nicotinic acid.

References Cited by the Examiner UNITED STATES PATENTS 2,834,786 9/1955 Mueller 260-2955 2,905,688 9/1959 Illich 260295.5 3,066,168 11/1962 Stengel 260-583 3,116,331 12/1963 Norton et al. 260-583 WALTER A. MODANCE, Primary Examiner. A. L. ROTMAN, Assistant Examiner. 

1. THE METHOD OF PREPARING NICOTINIC ACID WHICH COMPRIES REDUCTIVELY TRIMERIZING ACRYLONITRILE TO TRICYANOHEXANE, HYDROGENATING THE CYANO GROUPS, HEATING WITH DEHYDROGENATION CATALYST TO OBTAIN 3-(4-AMINOBUTYL)-PYRIDINE, AND OXIDIZING THE AMINOBUTYL GROUP TO A CARBOXYL GROUP TO OBTAIN NICOTINIC ACID. 